Synthesis and Angiotensin Converting Enzyme (ACE) inhibition activity of chalcones derivatives

Hypertension is a common and often progressive disorder that poses a major risk for cardiovascular and renal disease [1,2]. It is well recognized that the Renin–Angiotensin System (RAS) has an important role in cardiovascular physiology, water-electrolyte balance, and cell function. Excessive activation of this system has been considered to be a main cause of hypertension. Angiotensin Converting Enzyme (ACE) is the most important regulatory site of RAS [3]. Aldolic condensations of 3,4,5-trimethoxy-acetophenone with appropriately substituted benzaldehydes were carried for synthesize a set of chalcone derivatives with a series of substituents on the B-ring, using commercially available compounds. The in vitro ACE inhibitory activity was measured trough the cleavage of the chromophore-fluorophore labelled substrate dansyltriglycine by Angiotensin I-Converting Enzyme preparation from rabbit lung (EC 3.4.15.1) into dansylglycine, which is quantitatively measured by HPLC [4]. The most active compound was 7 (IC50 0.219 mM), it was substituted with amino group in position R1 and a methoxylic group in position R2. The high activity was conserved when the amino group was substituted with an hydroxylic group as in 4 (IC50 0.225 mM). Chalcone 5 showed an IC50 0.246 mM on ACE, this compound was characterized by an hydroxylic group in position R2 and a methoxylic group in position R1. The absence of hydroxylic group in position R1 as in 3 cause a reduction of ACE inhibition activity (IC50 0.574 mM) when you compared with 4. We believe that the current finding would be important start point for design of ACE inhibitor as new therapeutic agent. References: 1.Chalmers, J. (1999) Blood Press 8:9. 2.Odama, U. et al. (2000) J. Clin. Hypertens. 2:312. 3.Schricker, K. et al. (1994) Hypertension, 24:157. 4.Elbl, G. & Wagner, H. (1991) Planta Med. 57:137.